Depression is a devastating illness that affects approximately 12 to 17% of the population at some point during the lifetime of an individual (Kessler et al 1994). Despite the availability of a wide range of antidepressant drugs, 30% to 40% of patients with major depression fail to respond to first-line antidepressant (e.g., selective serotonin reuptake inhibitors [SSRIs]) treatment, despite adequate dosage, duration, and compliance. Thus there is a clear need to develop novel and improved therapeutics for major depression. Current pathophysiological theories regarding the neurobiology of depression include alterations in intracellular signaling cascades, and impairments of cellular plasticity and resilience. There is recent evidence suggesting that promoting growth factors such as brain derived neurotrophic factor (BDNF) may provide a mechanism for the treatment of depression. New information indicating modulation of glutamate receptors in the actions of antidepressant treatments suggests a novel approach to develop a new class of antidepressants. Studies have shown that the biarylpropylsulfonamide AMPA receptor potentiators (LY392098 and LY451616) have antidepressant effects in animal models of depression. Several studies have demonstrated that AMPA receptor activation can increase expression of BDNF both in vitro and in vivo. Thus, one possible new approach for the treatment of depression is to use an AMPA receptor potentiator. In this study we propose to compare the ampakine receptor potentiator Org 24448 to placebo for the treatment of major depression. Inpatients and outpatients (primarily outpatients), ages 21-55, with a diagnosis of major depression (without psychotic features), will be randomized to double-blind treatment to either Org 24448 or placebo for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 90 patients with acute major depression will be enrolled in the study in order to reach the goal of randomizing 70 patients in the controlled trial.